Emerging monoclonal antibodies against Clostridium difficile infection

ABSTRACT

Introduction: Clostridium difficile infections are characterized by a high recurrence rate despite antibiotic treatments and there is an urgent need to develop new treatments such as fecal transplantation and immonotherapy. Besides active immunotherapy with vaccines, passive immunotherapy has shown promise, especially with monoclonal antibodies.

Areas covered: Herein, the authors review the different assays performed with monoclonal antibodies against C. difficile toxins and surface proteins to treat or prevent primary or recurrent episodes of C. difficile infection in animal models and in clinical trials as well. Notably, the authors lay emphasis on the phase III clinical trial (MODIFY II), which allowed bezlotoxumab to be approved by the Food and Drug Administration and the European Medicines Agency. They also review new strategies for producing single domain antibodies and nanobodies against C. difficile and new approaches to deliver them in the digestive tract.

Expert opinion: Only two human Mabs against TcdA and TcdB have been tested alone or in combination in clinical trials. However, many animal model studies have provided rationale for the use of Mabs and nanobodies in C. difficile infection and pave the way for further clinical investigation.

KEYWORDS:

• Monoclonal antibodies
• single domain antibodies
• nanobodies
• Clostridium difficile treatment

Article highlights

• Several studies provide the rationale of passive immunotherapy with specific anti C. difficile polyclonal antibodies targeting the toxins or surface proteins to treat and/or prevent CDI.

• The protective role of antibodies against toxins has been demonstrated and several monoclonal antibodies against both toxins TcdA and TcdB have been produced, first, mouse monoclonal antibodies, then, human monoclonal antibodies.

• Two human monoclonal antibodies targeting the receptor-binding domain of TcdA (Actoxumab) and TcdB (bezlotoxumab) respectively have been tested in clinical trials. Phase III clinical trials (Funded by Merck; MODIFY I and MODIFY II)) showed that the anti-TcdB monoclonal antibody bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The Food and Drug Administration and the European Medicines Agency have approved it.

• Several monoclonal antibody subunits and nanobodies targeting both toxins have been produced. They have been tested in animal models but not yet in clinical trials.

• A combination of specific nanobodies recognizing different domains of both toxins is more able to have neutralization properties against C. difficile strains of diverse origins.

• A few nanobodies targeting the binary toxin and colonization factors have beenobtained and only tested in vitro.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript has not been funded.